WO2023178799A1 - 一种含有维生素k 2改善心血管钙化的药物组合物及其制备方法与应用 - Google Patents

一种含有维生素k 2改善心血管钙化的药物组合物及其制备方法与应用 Download PDF

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WO2023178799A1
WO2023178799A1 PCT/CN2022/090653 CN2022090653W WO2023178799A1 WO 2023178799 A1 WO2023178799 A1 WO 2023178799A1 CN 2022090653 W CN2022090653 W CN 2022090653W WO 2023178799 A1 WO2023178799 A1 WO 2023178799A1
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pharmaceutical composition
composition
vitamin
parts
active ingredients
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French (fr)
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何天明
史鲁秋
薛虹宇
苏桂珍
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南京盛德生物科技研究院有限公司
南京壹盛康品生物科技有限公司
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention relates to the technical fields of medicine, health products and food, and specifically relates to a pharmaceutical composition containing vitamin K2 for improving cardiovascular calcification and its preparation method and application.
  • Vascular calcification refers to inappropriate biological calcification that occurs in the soft tissues of the cardiovascular system. It is a pathological change in which calcium salts are deposited in the arterial wall tissue. It is prevalent in many diseases such as atherosclerosis, diabetes, kidney disease, aging, systolic hypertension, etc., and can easily lead to myocardial infarction and stroke.
  • Previous studies have considered vascular calcification to be a passive, degenerative, and inevitable terminal process. However, recent clinical and basic research results have shown that vascular calcification is similar to the process of bone development and cartilage formation and is an active, adjustable, and Processes that can be treated and prevented.
  • Coronary heart disease is the main killer that endangers the health and life of middle-aged and elderly people in today's society. With the progress of society and the improvement of civilization, the incidence rate of coronary heart disease is increasing year by year, and it is getting younger. Currently, nearly 200 million people around the world are using statins to prevent and treat coronary heart disease. The latest research has found that people who use statins frequently are more likely to exhibit symptoms of coronary heart disease than those who use statins less frequently. Acceleration of arterial calcification.
  • the main physiological mechanisms of "statins" drugs in promoting arterial calcification are: first, inhibiting the function of vitamin K, causing arterial calcium deposition; second, inhibiting the synthesis of coenzyme Q 10 in the body, leading to antioxidant The level of coenzyme Q 10 decreases, damaging mitochondrial energy metabolism, leading to a sharp decline in the body's antioxidant capacity, thereby inducing myocardial damage.
  • vitamin K 2 is generally used as a dietary supplement to promote calcium absorption, protect joint health, and strengthen bones. Its role in reversing calcification has not been taken seriously or is rarely used.
  • vitamin K2 is a fat-soluble vitamin with low solubility in water, intestinal absorption is difficult after oral administration and bioavailability is low.
  • vitamin K2 is extremely sensitive to light and heat, and the shelf life of conventional related products is unstable, and the biological activity is seriously reduced after long-term storage. Therefore, vitamin K 2 related products with stable activity, high bioavailability and targeted functions are urgently needed.
  • the purpose of the present invention is to provide a vitamin K 2 related product with stable activity, high bioavailability and targeted function in order to overcome the above-mentioned deficiencies in the existing technical field.
  • the present invention provides a pharmaceutical composition containing vitamin K 2 for improving cardiovascular calcification.
  • the pharmaceutical composition is composed of composition I, composition II, and composition III, wherein composition I is composed of a substance that promotes calcium Composed of absorbed active functional ingredients, composition II is composed of active functional ingredients that inhibit or reverse calcification, and composition III is composed of active functional ingredients that provide daily protection of cardiovascular health;
  • composition I, composition II and composition III The mass ratio of composition I, composition II and composition III is (0.1 ⁇ 5): (0.01 ⁇ 0.5): (100 ⁇ 500).
  • the composition I is composed of active ingredients that promote calcium absorption, wherein the active ingredients include main active ingredients and auxiliary active ingredients, wherein the main active ingredient is vitamin D 3 and the auxiliary active ingredients are lactose, One or more of vitamin A, albumin peptide, vitellogenin peptide, fructooligosaccharide, galacto-oligosaccharide, and ⁇ -carotene.
  • the composition II is composed of active ingredients that inhibit or reverse calcification, wherein the active ingredients include a main active ingredient and an auxiliary active ingredient.
  • the main active ingredient is vitamin K 2 and the auxiliary active ingredient It is one or more of naringenin, arachidonic acid, triptolide, puerarin, apigenin and aconite polysaccharide.
  • the composition III is composed of active ingredients that provide daily cardiovascular health protection, wherein the active ingredients include main active ingredients and auxiliary active ingredients, and the main active ingredients are omega-3 fatty acids, pyrroloquinoline Quinone, coenzyme Q 10 , auxiliary active ingredients are epicatechin, pumpkin seed oil, phospholipids, krill oil, spirulina, quercetin, lycopene, pomegranate polyphenols, resveratrol, cyanidin, One or more of soy isoflavones and allicin.
  • the active ingredients include main active ingredients and auxiliary active ingredients, and the main active ingredients are omega-3 fatty acids, pyrroloquinoline Quinone, coenzyme Q 10 , auxiliary active ingredients are epicatechin, pumpkin seed oil, phospholipids, krill oil, spirulina, quercetin, lycopene, pomegranate polyphenols, resveratrol, cyanidin, One or more of soy isoflavon
  • the composition I accounts for 0.1% to 1% of the total mass of the pharmaceutical composition; the composition II accounts for 0.001% to 0.1% of the total mass of the pharmaceutical composition; and the composition III accounts for all 30% to 85% of the total mass of the pharmaceutical composition.
  • the pharmaceutical composition also includes an auxiliary material part, and the auxiliary material is microcrystalline cellulose, silicon dioxide, magnesium stearate, ⁇ -cyclodextrin, mannitol, carboxymethylcellulose sodium, hydroxymethylcellulose, Propylcellulose, glycerin, gelatin, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, talc, modified starch, antioxidant, titanium dioxide, lemon yellow aluminum lake, sunset yellow aluminum lake, One or more of carmine aluminum lake, brown iron oxide, triacetin, polyethylene glycol, crospovidone, and croscarmellose sodium.
  • the pharmaceutical composition contains the following main components in parts by mass: 0.01 to 1 part of vitamin K 2 , 300 to 3000 parts of omega-3 fatty acids, 1 to 40 parts of pyrroloquinoline quinone, and 10 to 500 parts of coenzyme Q 10 1 to 60 servings of vitamin D 3 .
  • the vitamin K2 is in the form of MK-7 with an all-trans structure; the ratio of EPA and DHA in the omega-3 fatty acid is (0.1-4):1.
  • the present invention also provides the application of the above pharmaceutical composition in dietary supplements and health products.
  • the present invention provides a soft capsule containing any of the above pharmaceutical compositions containing vitamin K2 for improving cardiovascular calcification.
  • the soft capsule contains the following components by mass: 0.01-0.7 parts of vitamin K2 , 500-2500 parts of omega-3 fatty acids, 1-30 parts of pyrroloquinoline quinone, and coenzyme Q 10 50-500 parts, vitamin D 3 1-50 parts, soft capsule skin 50-500 parts, enteric coating powder 10-100 parts, excipients 20-200 parts.
  • the present invention also provides a preparation method of the above-mentioned soft capsule, and the preparation method includes the following steps:
  • Granulation Under light-proof conditions, mix the non-fat-soluble components of the above-mentioned composition II and composition III with some auxiliary materials evenly, and use dry granulation to control the particle size between 50 and 200 mesh to obtain granulated granules;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Cystic fluid Weigh the fat-soluble components in composition III, composition I and the antioxidants in the excipients by weight, and dissolve the antioxidants and composition I in the fat of composition III respectively at a temperature of 20 to 60°C. From the oil with soluble components, a mixed oil liquid is obtained, and the cyst liquid is obtained by letting it stand for 4 to 12 hours to deaeration;
  • Soft capsule skin The soft capsule skin is made using common formulas and preparation methods in this industry;
  • Soft capsule Inject the capsule liquid of step (4) between the two layers of capsule skin containing the coated tablet of step (3), and press the pill to obtain a soft capsule containing the tablet inside.
  • the product obtained by this preparation method avoids the influence of light, heat, acid and other environments as well as the first-pass effect of the oral cavity and gastrointestinal tract, and avoids premature decomposition after ingestion. Therefore, the combination
  • the activity of MK-7 and other functional ingredients in the product is more stable and lasting, the bioavailability is higher, the product quality is more stable, and the shelf life is longer;
  • Figure 1 shows the trend of the influence of pharmaceutical compositions on OPG (osteoprotegerin) levels in rat serum
  • Figure 2 shows the trend of the influence of pharmaceutical compositions on OPN (serum osteopontin) levels in rat serum;
  • Figure 3 shows the trend change of the effect of pharmaceutical compositions on CaBP (calcium binding protein) levels in rat serum
  • Figure 4 shows the trend change of the influence of pharmaceutical compositions on BMP-7 (bone morphogenetic protein-7) levels in rat serum;
  • Figure 5 shows the trend of the effect of pharmaceutical compositions on calcium content levels in arterial blood vessels of rats.
  • the invention provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification and a preparation method thereof.
  • the pharmaceutical composition can comprehensively prevent and block cardiovascular calcification, and is especially suitable for reversing the effects of taking statins. Treats cardiovascular calcification symptoms caused by similar drugs while providing daily support and protection for heart health.
  • the present invention improves cardiovascular calcification from three perspectives: targeted promotion of calcium absorption, reversal of calcification and daily protection. On the one hand, it promotes the absorption of calcium to avoid inappropriate accumulation of calcium in the blood vessel wall; on the other hand, it strengthens and promotes the transformation of calcium that has been deposited incorrectly; on the third hand, by strengthening mitochondrial energy metabolism, it improves myocardial capacity, enhances resistance, and avoids body damage, so as to achieve the goal.
  • the three angles work synergistically to achieve the overall effect of improving cardiovascular calcification.
  • the present invention provides a pharmaceutical composition containing vitamin K 2 for improving cardiovascular calcification.
  • the pharmaceutical composition consists of composition I, composition II, and composition III,
  • composition I, composition II and composition III The mass ratio of composition I, composition II and composition III is (0.1 ⁇ 5): (0.01 ⁇ 0.5): (100 ⁇ 500).
  • composition I is composed of active ingredients that promote calcium absorption, and may include one of lactose, vitamin A, vitamin D 3 , albumin polypeptide, egg yolk protein peptide, fructooligosaccharide, galacto-oligosaccharide, and ⁇ -carotene. kind or variety.
  • Vitamin D 3 also known as cholecalciferol, is a type of vitamin D that can improve the body's absorption of calcium and phosphorus and bring the levels of plasma calcium and plasma phosphorus to saturation.
  • Vitamin D 3 is the precursor of D hormone and needs to be hydroxylated in the kidneys and lungs to become active vitamin D, and active vitamin D acts in the kidneys and intestines to promote calcium reabsorption. Therefore, the present invention prefers the compounding of VD 3 and MK-7. On the one hand, it can promote the absorption of calcium and avoid excessive deposition of absorbed calcium.
  • MK-7 activates osteocalcin and acts as a calcium claw to remove the deposited calcium. Captures bones, blocks and prevents calcification.
  • vitamin D 3 is used as the main component of composition I of the present invention.
  • the vitamin D 3 in the present invention is of plant-based origin, and the effective activity unit is ⁇ 400IU.
  • composition II is composed of active ingredients capable of inhibiting or reversing calcification, and may include one or more of naringenin, arachidonic acid, triptolide, puerarin, apigenin, aconite polysaccharide, and vitamin K2 . kind.
  • Vitamin K2 is a type of fat-soluble vitamin mainly used to treat and prevent osteoporosis. According to the length of the tail chain, K 2 is divided into subcategories such as MK-4, MK-7, MK-8, and MK-10. All vitamin K2 are similar in structure but differ in side chain length. The longer the side chain, the better the absorption, the higher the biological activity, and the longer it exists in the blood. Therefore, the long-chain form of MK-7 is the best, has been shown to have the highest bioavailability, and has a long half-life after oral ingestion, allowing its benefits to be exerted over a longer period of time. And MK-7 is obtained through plant fermentation, which has a healthier source.
  • Osteocalcin also known as bone ⁇ -carboxyglutamic acid protein, is a protein secreted by osteoblasts. It is a vitamin K-dependent protein and is the specific executor of calcium into the bone. It has no physiological activity when it is first secreted and must undergo a carboxylation reaction to exert its physiological effects. After carboxylation, calcium salts can be firmly grasped, promoting the deposition of calcium salts in bones and increasing the bone mineralization rate. Therefore, vitamin K 2 is crucial to maintaining bone health and preventing and treating osteoporosis. If the body lacks vitamin K 2 , osteocalcin cannot form calcium claws, just like a human hand without a thumb, the ability to grasp is reduced, and a large amount of calcium will be lost from the bones, leading to osteoporosis.
  • the carboxylated matrix ⁇ -carboxyglutamic acid protein can prevent the deposition of calcium in soft tissues such as blood vessels and cartilage, and can combine with calcium ions deposited on the blood vessel wall to move it out of the blood vessels, thereby improving arterial calcification.
  • the present invention preferably utilizes vitamin K 2 to activate osteocalcin and accurately capture erroneously deposited calcium as the core difference point to achieve the purpose of targeted blocking and prevention of cardiovascular calcification.
  • the vitamin K 2 has an MK-7 structure and is obtained through organic legume fermentation. Compared with the chemical synthesis method, there is no organic reagent residue, the whole process is green, and it is safer to take;
  • the MK-7 is an all-trans structure with a purity of ⁇ 99.5%, and the bioavailability of MK-7 in the trans structure is higher.
  • the composition III is composed of active ingredients that provide daily cardiovascular health protection, and may include omega-3 fatty acids, pyrroloquinoline quinone (PQQ), coenzyme Q 10 (CoQ 10 ), epicatechin, pumpkin seed oil, and phospholipids , krill oil, spirulina, quercetin, lycopene, pomegranate polyphenols, resveratrol, cyanidin, soy isoflavones, and one or more of allicin.
  • active ingredients that provide daily cardiovascular health protection, and may include omega-3 fatty acids, pyrroloquinoline quinone (PQQ), coenzyme Q 10 (CoQ 10 ), epicatechin, pumpkin seed oil, and phospholipids , krill oil, spirulina, quercetin, lycopene, pomegranate polyphenols, resveratrol, cyanidin, soy isoflavones, and one or more of allicin.
  • Coenzyme Q 10 is a fat-soluble quinone with a structure similar to vitamin K. It is named after the polymerization degree of the side chain at the sixth position of the mother core - polyisopentenyl group, which is 10. It is a quinone ring compound. Studies have shown that cholesterol-lowering statins can reduce coenzyme Q 10 levels in the body by up to 40%, making heart problems more serious. While taking statins, supplementing with coenzyme Q 10 can reduce this side effect of statins, relieve myalgia and fatigue caused by the drugs, and protect the liver. At the same time, Coenzyme Q 10 can activate human cells and produce energy, and has functions such as improving immunity, enhancing antioxidants, delaying aging, and enhancing human vitality.
  • PQQ is produced by Gram-negative bacteria, has a wide range of nutritional effects on microorganisms, animals and plants, and has antioxidant nutrients.
  • the protective effect of PQQ on the heart is related to its ability to scavenge free radicals.
  • PQQ can scavenge reactive oxygen species produced by hypoxia-reperfusion and significantly reduce the release of lactate dehydrogenase in the heart.
  • its catalytic product Under the catalysis of flavin reductase, its catalytic product can also reduce the peroxidation status of hemoglobin and eliminate the effects of hypoxia-reperfusion. Myocardial damage.
  • PQQ can significantly reduce the scope of myocardial infarction, enhance left ventricular pressure and left ventricular diastolic pressure rise and fall rates, reduce ventricular fibrillation, and reduce malondialdehyde levels in myocardial tissue.
  • PQQ can also inhibit the production of ROS induced by hydrogen peroxide in rat cardiomyocytes and the decrease in mitochondrial membrane potential, thereby reducing oxidative stress, inhibiting the inactivation of mitochondrial function, and protecting rat cardiomyocytes.
  • the present invention is aimed at the characteristics of long-term use of statins to reduce the level of coenzyme Q 10 in the body. It is preferable to compound PQQ and CoQ 10. On the one hand, it can increase the level of coenzyme Q 10 in the body. On the other hand, it can activate cells, strengthen mitochondrial energy metabolism, and improve myocardial metabolism. ability to avoid drug damage. At the same time, both PQQ and CoQ 10 can improve the body's antioxidant capacity and maintain a balance in scavenging free radicals.
  • PQQ can be the disodium salt form of pyrroloquinoline quinone or the acid form of pyrroloquinoline quinone, with a purity of ⁇ 99%.
  • the purity of CoQ10 is ⁇ 98%.
  • Omega-3 is a long-chain, polyunsaturated fatty acid found in plants and marine organisms.
  • Existing research data shows that omega-3s can promote heart health and prevent coronary artery disease. It mainly protects the inner wall cells of blood vessels, restores blood vessel elasticity, relaxes blood vessels, and inhibits platelet aggregation. While lowering blood lipids, it also lowers blood pressure and inhibits the formation of thrombus, thereby effectively preventing and treating cardiovascular and cerebrovascular diseases.
  • omega-3 can also prevent arrhythmias and prevent sudden cardiac death.
  • omega-3 fatty acids including alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
  • EPA can prevent the occurrence of stroke or myocardial infarction, lower blood cholesterol and prevent arteriosclerosis.
  • DHA has the function of activating brain cells, promoting the coordination of neural circuit conduction, and maintaining the normal operation of brain cells. DHA supplementation can improve concentration loss, learning disabilities, memory loss, and Alzheimer's disease.
  • omega-3 also has the effects of fighting neurological diseases, preventing and fighting cancer, and anti-inflammatory. Therefore, using omega-3 supplements as part of lifestyle intervention in the pharmaceutical composition of the present invention can reduce the mortality and risk of sudden cardiac death in the population.
  • the ratio of EPA:DHA in omega-3 fatty acids is (0.1-4):1;
  • the content of EPA in omega-3 fatty acids is ⁇ 40%;
  • the content of EPA in the omega-3 fatty acid is ⁇ 45%.
  • the present invention found that in this field, there are many active ingredients or dietary supplements that can comprehensively block and prevent cardiovascular calcification, but it is not a simple combination that can achieve the purpose of synergy. For this reason, the present invention starts from the mechanism of calcification, cardiovascular diseases and the metabolic characteristics of statins, and selects the above-mentioned components through a large number of experiments for compounding. On the one hand, it can promote the absorption of calcium and avoid the accumulation of excess calcium on the blood vessel wall; on the other hand, it can promote the absorption of calcium and avoid the accumulation of excess calcium on the blood vessel wall.
  • the pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification contains the following components by mass: vitamin K 2 (MK-7) 0.01 ⁇ 1 part, 300-3000 parts of omega-3 fatty acids, 1-40 parts of pyrroloquinoline quinone (PQQ), 10-500 parts of coenzyme Q 10 (CoQ 10 ), 1-60 parts of vitamin D 3 (VD 3 ).
  • the composition also includes auxiliary materials, which are essential auxiliary materials for preparing the pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification provided by the present invention, including Coating powder, antioxidant, lubricant, capsule skin.
  • auxiliary materials which are essential auxiliary materials for preparing the pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification provided by the present invention, including Coating powder, antioxidant, lubricant, capsule skin.
  • the auxiliary materials are microcrystalline cellulose, silicon dioxide, magnesium stearate, ⁇ -cyclodextrin, mannitol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, glycerin, gelatin, Methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, talc, modified starch, antioxidant, titanium dioxide, lemon yellow aluminum lake, sunset yellow aluminum lake, carmine aluminum lake, brown iron oxide , one or more of triacetin, polyethylene glycol, crospovidone, and croscarmellose sodium.
  • the dosage form of the pharmaceutical composition is one or more of tablets, powders, hard capsules, soft capsules, and suspensions.
  • the second aspect of the present invention provides the application of the above-mentioned pharmaceutical composition containing vitamin K 2 to improve cardiovascular calcification in dietary supplements and health products.
  • the present invention provides a soft capsule containing the above-mentioned pharmaceutical composition containing vitamin K2 for improving cardiovascular calcification.
  • the soft capsule contains the following components by mass: 0.01 to 0.7 parts of vitamin K 2 (MK-7), 500 to 2500 parts of omega-3 fatty acids, 1 to 30 parts of pyrroloquinoline quinone (PQQ), and coenzyme 50 to 500 parts of Q 10 (CoQ 10 ), 1 to 50 parts of vitamin D 3 (VD 3 ), 50 to 500 parts of soft capsule skin, 10 to 100 parts of enteric coating powder, and 20 to 200 parts of excipients.
  • MK-7 vitamin K 2
  • PQQ pyrroloquinoline quinone
  • CoQ 10 coenzyme 50 to 500 parts of Q 10
  • VD 3 vitamin D 3
  • 50 to 500 parts of soft capsule skin 10 to 100 parts of enteric coating powder, and 20 to 200 parts of excipients.
  • the present invention provides a method for preparing the above-mentioned pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification.
  • the preparation method is:
  • Granulation Under light-proof conditions, mix the non-fat-soluble ingredients in composition II and composition III with some auxiliary materials evenly, and use dry granulation to control the particle size between 50 and 200 mesh to obtain granulated granules;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Cystic fluid Weigh the fat-soluble components in composition III, composition I and the antioxidants in the excipients by weight, and dissolve the antioxidants and composition I in the fat of composition III respectively at a temperature of 20 to 60°C. From the oil with soluble components, a mixed oil liquid is obtained, and the cyst liquid is obtained by letting it stand for 4 to 12 hours to deaeration;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet.
  • the preparation method of the present invention also includes further processing methods, including but not limited to drying, pill washing, pill picking, packaging, etc., to finally obtain the finished product.
  • the product obtained by this preparation method avoids the influence of light, heat, acid and other environments as well as the first-pass effect of the mouth and stomach, and avoids premature decomposition after ingestion. Therefore, the MK in the composition
  • the activity of -7 and other active ingredients is more stable and lasting, the bioavailability is higher, the product quality is more stable, and the shelf life is longer.
  • the third aspect of the present invention provides the use of the above-mentioned pharmaceutical composition containing vitamin K 2 (MK-7) to improve cardiovascular calcification in dietary supplements and health products.
  • MK-7 vitamin K 2
  • This embodiment provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • vitamin K 2 MK-7
  • 1200 parts of omega-3 fatty acids 10 parts of PQQ
  • 200 parts of coenzyme Q 10 CoQ 10
  • 5 parts of vitamin D 3 VD 3
  • enteric coated 100 parts of coating powder and 50 parts of excipients.
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 100 mesh to obtain granulated particles;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Capsule liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 40°C to obtain a mixed oil. , let it stand for 12 hours to defoam and obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • This embodiment provides a pharmaceutical composition containing vitamin K2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • vitamin K 2 MK-7
  • 600 parts of omega-3 fatty acids 10 parts of PQQ
  • 100 parts of coenzyme Q 10 CoQ 10
  • 2 parts of vitamin D 3 VD 3
  • 150 parts of soft capsule skin enteric-coated 80 parts of coating powder and 30 parts of excipients.
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 120 mesh to obtain granulated particles;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Capsule liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 40°C to obtain a mixed oil. , let it stand for 12 hours to defoam and obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • This embodiment provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • vitamin K 2 MK-7
  • 900 parts of omega-3 fatty acids 15 parts of PQQ, 150 parts of coenzyme Q 10 (CoQ 10 ), 3 parts of vitamin D 3 (VD 3 ), 180 parts of soft capsule skin, enteric coated 70 parts of coating powder and 40 parts of excipients.
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 80 mesh to obtain granulated granules;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Cyst liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 50°C to obtain a mixed oil. , let it stand for 12 hours to defoam and obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • This embodiment provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 100 mesh to obtain granulated particles;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Cyst liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 45°C to obtain a mixed oil. , let it stand for 8 hours for deaeration to obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • This embodiment provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 120 mesh to obtain granulated particles;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Capsule liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 40°C to obtain a mixed oil. , let it stand for 10 hours to defoam and obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • This embodiment provides a pharmaceutical composition containing vitamin K 2 (MK-7) for improving cardiovascular calcification, which contains the following components in parts by weight:
  • vitamin K 2 MK-7
  • 1500 parts of omega-3 fatty acids 18 parts of PQQ
  • 180 parts of coenzyme Q 10 CoQ 10
  • 10 parts of vitamin D 3 VD 3
  • enteric-coated package 80 parts of clothing powder and 60 parts of accessories.
  • Granulation Under light-proof conditions, mix MK-7, PQQ and tableting excipients in equal proportions, and use dry granulation to control the particle size to 100 mesh to obtain granulated particles;
  • Coated tablets Mix the bare tablets prepared in step (2) with the enteric coating powder in a coating pot, and follow the normal coating steps to prepare coated tablets;
  • Capsule liquid Weigh ⁇ -3, CoQ 10 , VD 3 and antioxidants by weight, dissolve the antioxidants, CoQ 10 and VD 3 in ⁇ -3 oil respectively at a temperature of 40°C to obtain a mixed oil. , let it stand for 11 hours for deaeration to obtain the cyst fluid;
  • Soft capsule skin The soft capsule skin is prepared using common formulas and preparation methods in this industry;
  • Soft capsule Use special equipment to inject the capsule liquid in step (4) between the two layers of capsule skin containing the coated tablet in step (3), and press the pill through a special mold to obtain a soft capsule containing the tablet. capsule.
  • Example 4 The soft capsules prepared in Example 4, Example 5, and Example 6 were respectively taken as the experimental group, and the commercial vitamin K 2 (MK-7) soft capsules (MK-7 content 90 ⁇ g) were purchased as the control group. Put into sealed brown vial. Place it in a constant temperature and humidity box at 40 ⁇ 2°C and 75% ⁇ 5%RH environment, and do accelerated experiments. Samples were taken at 0, 1, 2, 3, 4, 5, 6, and 9 months to measure the MK-7 content. MK-7 content was determined by high performance liquid chromatography. The accelerated stability test results are as follows.
  • Rats were randomly divided into normal control group (10 rats) and dexamethasone injection group (100 rats) according to body weight.
  • the rats in the dexamethasone injection group were intramuscularly injected with dexamethasone 2.5 mg/kg three times a week, and the normal control group was intramuscularly injected with a corresponding volume of normal saline. After 6 weeks of continuous injection, the injection was stopped.
  • the rats were fasted for 24 hours, blood was taken from the orbital vein, and the serum was separated.
  • a fully automatic biochemical analyzer was used to measure the serum alkaline phosphatase (ALP) level of the rats.
  • the ALP level of the rats in the dexamethasone injection group was compared with that of the rats in the normal control group.
  • ALP serum alkaline phosphatase
  • the rats that were successfully modeled were randomly divided into 5 groups: model group, positive control group (pure product MK-7100 ⁇ g/kg), and experimental group (Example 4, Example 5, and Example 6).
  • the normal control group and the model group were given 10 mg/kg edible oil by gavage.
  • the experimental group was given the corresponding MK-7 according to the established embodiment.
  • the positive control group was given MK-7 (12 mg/kg) dissolved in edible oil by gavage every day. , once a day for 6 weeks. Rats in each group were housed in separate cages, with free access to food and water, and the room temperature was kept constant at (22 ⁇ 2)°C.
  • vascular calcium content Dissolve 10 mg of abdominal aorta in nitric acid, digest it, dry it, reconstitute it with deionized water containing 27 nmol/L KCL and 27 ⁇ mol/L LaCl 3 , and read it with an atomic spectrophotometer at 442.7 nm. Absorbance, converted into tissue calcium content ( ⁇ mol/mg.dw).
  • the vascular blood calcium level of the rats in the model group increased significantly; compared with the model group, the rats in the experimental group (Example 4), experimental group (Example 5), and experimental group (Example 6) Vascular calcium levels were significantly reduced with significant variability.
  • OPN serum osteopontin
  • OPG osteoprotegerin
  • BMP-7 bone morphogenetic protein-7
  • CaBP calcium-binding protein
  • the pharmaceutical composition of the present invention can regulate the bone marrow function by significantly increasing the levels of OPN (serum osteopontin), OPG (osteoprotegerin), CaBP (calcium binding protein) and BMP-7 (bone morphogenetic protein-7). Inhibits vascular calcification, thereby reducing blood vessel calcium content.
  • OPN serum osteopontin
  • OPG osteoprotegerin
  • CaBP calcium binding protein
  • BMP-7 bone morphogenetic protein-7

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Abstract

一种含有维生素K 2改善心血管钙化的药物组合物，所述药物组合物由组成物Ⅰ、组成物Ⅱ、组成物Ⅲ构成，其质量比为(0.1～5)：(0.01～0.5)：(100～500)。还提供了该药物组合物的制备方法及其应用。所述药物组合物能全面预防和阻断心血管钙化，尤其适合于逆转由于服用他汀类药物导致的心血管钙化症状，同时提供心脏健康日常支持保护作用。药物组合物各活性成分稳定、生物利用度高、靶向性强，无副作用，能同时达到预防和治疗的目的。

Description

一种含有维生素K 2改善心血管钙化的药物组合物及其制备方法与应用 技术领域
本发明涉及医药、保健品及食品技术领域，具体涉及一种含有维生素K 2改善心血管钙化的药物组合物及其制备方法与应用。
背景技术
血管钙化是指发生于心血管系统软组织内的不适当生物钙化，是钙盐沉积在动脉壁组织的一种病理改变。在动脉粥样硬化、糖尿病、肾病、衰老、收缩性高血压等多种疾病中普遍存在，极易导致心肌梗塞和脑中风等。既往研究认为血管钙化是一个被动的、退化的、不可避免的终末过程，但最近临床和基础研究结果表明，血管钙化类似于骨发育和软骨形成的过程，是一个主动的、可调节的、可治疗和预防的过程。
冠心病是当今社会危害中老年健康和生命的主要杀手，随着社会的进步和文明程度的提高，冠心病的发病率逐年上升，并呈年轻化趋势。目前，全球有接近2亿人口正在使用“他汀”类药物来预防和治疗冠心病，最新的研究发现，与低频使用他汀类药物者相比，高频使用他汀类药物的人更容易表现出冠状动脉钙化的加速。
基于现有药理学证据和临床试验结果，“他汀”类药物促进动脉钙化的主要生理机制：一是抑制维生素K的功能，引起动脉钙沉积；二是抑制体内辅酶Q 10的合成，导致抗氧化的辅酶Q 10水平下降，损伤线粒体能量代谢，导致机体的抗氧化能力急剧下降，从而诱发心肌损伤。
因此，全面阻断和预防心血管的钙化，是保证服用他汀类药物人群健康，减少副作用，提高生命质量的重要关键。
目前维生素K 2一般用来作为膳食补充剂促进钙的吸收，保护关节健康、强健骨骼，其逆转钙化的作用未被重视或极少应用。同时由于维生素K 2是脂溶性维生素，在水中溶解度小，口服后肠道吸收困难，生物利用度低。且维生素K 2对光和热极其敏感，常规相关产品货架期不稳定，长时间储存后生物活性降低严重。因此，亟需活性稳定，生物利用率高且功能靶向的维生素K 2相关产品。
发明内容
本发明的目的在于为克服现有技术领域的上述不足，提供一种活性稳定、生物利用率高且功能靶向的维生素K 2相关产品。
为实现上述目的，本发明提供如下技术方案：
在一个方面，本发明提供了一种含有维生素K 2改善心血管钙化的药物组合物，所述药物组合物由组成物Ⅰ、组成物Ⅱ、组成物Ⅲ构成，其中组成物Ⅰ由具有促进钙吸收的活性功能成分组成，组成物Ⅱ由具有抑制或逆转钙化的活性功能成分组成，组成物Ⅲ由提供心血管健康日常保护的活性功能成分组成；
所述组成物Ⅰ、组成物Ⅱ、组成物Ⅲ的质量比为(0.1～5)：(0.01～0.5)：(100～500)。
在一些实施方案中，所述组合物Ⅰ由具有促进钙吸收的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，其中主要活性成分为维生素D 3，辅助活性成分为乳糖、维生素A、清蛋白多肽、卵黄蛋白肽、低聚果糖、低聚半乳糖、β-胡萝卜素中的一种或者多种。
在另一些实施方案中，所述组合物Ⅱ由具有抑制或者逆转钙化的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，所述主要活性成分为维生素K 2，辅助活性成分为柚皮素、花生四烯酸、雷公藤红素、葛根素、芹菜素、附子多糖中的一种或者多种。
在又一些实施方案中，所述组成物Ⅲ由提供心血管日常健康保护的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，主要活性成分为Ω-3脂肪酸、吡咯喹啉醌、辅酶Q 10，辅助活性成分为表儿茶素、南瓜籽油、磷脂、磷虾油、螺旋藻、槲皮素、蕃茄红素、石榴多酚、白藜芦醇、矢车菊素、大豆异黄酮、大蒜素中的一种或者多种。
优选地，所述组成物Ⅰ占所述药物组合物总质量的0.1％～1％；所述组成物Ⅱ占所述药物组合物总质量的0.001％～0.1％；所述组成物Ⅲ占所述药物组合物总质量的30％～85％。
另外优选地，所述药物组合物还包括辅料部分，所述辅料为微晶纤维素、二氧化硅、硬脂酸镁、α-环糊精、甘露糖醇、羧甲基纤维素钠、羟丙基纤维素、甘油、明胶、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、滑石粉、变性淀粉、抗氧化剂、二氧化钛、 柠檬黄铝色淀、日落黄铝色淀、胭脂红铝色淀、棕氧化铁、三乙酸甘油酯、聚乙二醇、交联聚维酮、交联羧甲基纤维素钠中的一种或者多种。
更优选地，所述药物组合物包含以下质量份的主要组分：维生素K 20.01～1份、Ω-3脂肪酸300～3000份、吡咯喹啉醌1～40份、辅酶Q 1010～500份、维生素D 31～60份。
在更优选的实施方案中，所述维生素K 2为具有全反式结构的MK-7形式；所述Ω-3脂肪酸中EPA和DHA的比例为(0.1～4)：1。
本发明在另一方面还提供了上述药物组合物在膳食补充剂、保健品中的应用。
在第三方面，本发明提供了一种软胶囊，所述软胶囊含有上述任一种含有维生素K2改善心血管钙化的药物组合物。
在上述软胶囊的优选实施例中，所述软胶囊包含以下质量份的组分：维生素K 20.01～0.7份、Ω-3脂肪酸500～2500份、吡咯喹啉醌1～30份、辅酶Q 1050～500份、维生素D 31～50份、软胶囊皮50～500份、肠溶包衣粉10～100份、辅料20～200份。
本发明在第四方面还提供了上述软胶囊的制备方法，所述制备方法包括如下步骤：
(1)制粒：在避光条件下，将如上所述的组成物Ⅱ、组成物Ⅲ中非脂溶性成分与部分辅料混合均匀，采用干法制粒，粒径控制在50～200目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液：按重量称取组成物Ⅲ中脂溶性成分、组成物Ⅰ和辅料中的抗氧化剂，在20～60℃温度下将抗氧化剂和组成物Ⅰ分别溶于组成物Ⅲ中脂溶性成分的油中，得到混合油液，静置4～12h脱泡得到囊液；
(5)软胶囊皮：采用本行业通用配方和制备方法制得软胶囊皮；
(6)软胶囊：将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，压丸，得到内含有片剂的软胶囊。
与现有技术相比，本发明的有益效果是：
(1)能靶向阻断和预防心血管钙化：一方面促进钙的吸收、避免血管壁多余钙的积累，另一方面加强已经沉积错误的钙的转化，第三方面通过加强线粒体能量代谢，提 高心肌能力、增强抵抗、避免机体损伤，从而从宏观上进行提前预防，阻断风险源头和提供预案保护措施。在改善血管钙化的同时，也能预防和消除血管钙化带来的其他风险；
(2)采用本制备方法得到的产品，由于特殊的双重保护方式，避免了光、热、酸等环境的影响以及口腔、胃肠的首过效应，避免摄入后被过早分解，因此组合物中的MK-7及其他功能成分的活性更稳定持久，生物利用率更高，产品质量更稳定，货架期更长；
(3)在改善钙化的同时，还有提高机体免疫力、抗氧化、防癌、抗衰老、强健骨骼的作用。
附图说明
图1示出了药物组合物对大鼠血清中OPG(护骨素)水平的影响趋势变化；
图2示出了药物组合物对大鼠血清中OPN(血清骨桥蛋白)水平的影响趋势变化；
图3示出了药物组合物对大鼠血清中CaBP(钙结合蛋白水平的影响趋势变化；
图4示出了药物组合物对大鼠血清中BMP-7(骨形态发生蛋白-7)水平的影响趋势变化；
图5示出了药物组合物对大鼠动脉血管钙含量水平的影响趋势变化。
具体实施方式
下面将结合本发明实施例和附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明提供了一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物及其制备方法，所述药物组合物能全面预防和阻断心血管钙化，尤其适合于逆转由于服用他汀类药物导致的心血管钙化症状，同时提供心脏健康日常支持保护作用。
本发明从靶向促进钙吸收、逆转钙化、日常防护三个角度起到改善心血管钙化的效果。一方面促进钙的吸收避免钙在血管壁的不恰当积累，另一方面加强促进已经沉积错误钙的转化，第三方面通过加强线粒体能量代谢，提高心肌能力，增强抵抗，避免机体损伤，达到从宏观上进行提前预防，阻断风险源头和提供预案保护措施的效果。三个角 度协同作用，整体上达到改善心血管钙化的作用。
在一个方面，本发明提供一种含有维生素K 2改善心血管钙化的药物组合物，所述药物组合物由组成物Ⅰ、组成物Ⅱ、组成物Ⅲ构成，
所述组成物Ⅰ、组成物Ⅱ、组成物Ⅲ的质量比为(0.1～5)：(0.01～0.5)：(100～500)。
所述组合物Ⅰ由具有促进钙吸收的活性成分组成，可以包括乳糖、维生素A、维生素D 3、清蛋白多肽、卵黄蛋白肽、低聚果糖、低聚半乳糖、β-胡萝卜素中的一种或者多种。
维生素D 3又名胆钙化醇，是维生素D的一种，能提高机体对钙、磷的吸收，使血浆钙和血浆磷的水平达到饱和程度。研究表明，维生素D 3是D激素的前体，需要在肾脏和肺进行羟化变成活性的维生素D，而活性维生素D作用在肾脏和肠道促进钙的重吸收。因此，本发明优选VD 3和MK-7复配，一方面可以促进钙的吸收，避免吸收的钙过量沉积，另一方面发挥MK-7活化骨钙素作用，充当钙爪，将沉积的钙抓取到骨骼，阻断和预防钙化。
优选的，将维生素D 3作为本发明组成物Ⅰ的主体成分。
进一步优选地，本发明中维生素D 3为植物基来源，有效活性单位≥400IU。
所述组合物Ⅱ由具有抑制或者逆转钙化的活性成分组成，可以包括柚皮素、花生四烯酸、雷公藤红素、葛根素、芹菜素、附子多糖、维生素K 2中的一种或者多种。
维生素K 2是一类脂溶性维生素，主要用于治疗和预防骨质疏松症。根据尾链长度的不同，K 2又分为MK-4、MK-7、MK-8、MK-10等子类。所有维生素K 2在结构上相似，但侧链长度不一样。侧链越长吸收越好，生物活性越高，在血液中存在时间也越长。因此，长链的MK-7是最优质的，它被证明具有最高的生物利用度，且在口服摄入后具有较长的半衰期，从而能够在较长时间周期内发挥它的益处。并且MK-7是通过植物发酵获得，具有更为健康的来源。
骨钙素又称骨γ-羧基谷氨酸蛋白，是由成骨细胞分泌的一种蛋白质，是一种维生素K依赖性蛋白，它是领钙入骨的具体执行者。它刚分泌出来时没有生理活性，必须经过羧化反应才能发挥生理作用。经过羧化后，才能牢固地抓住钙盐，促进钙盐在骨骼中的沉积，提高骨矿化速率。因此，维生素K 2对维持骨骼健康、防治骨质疏松显得至关重 要。如果机体缺乏维生素K 2，骨钙素不能形成钙爪，就像人的手没有大拇指一样，抓握的能力下降，大量钙就会从骨骼中流失，导致骨质疏松。
血液中钙离子除了参与正常的机体功能和代谢，大部分有两种不同的去向：(1)沉积在正确的部位，比如骨骼、牙齿等；(2)沉积在错误的部位：包括关节软骨、心脑动脉血管、胆囊和肾脏等软组织。错误沉积的钙质会造成所在部位组织和器官的功能损害。这些血钙如果不能大部分迁移到骨骼，就会大量在血管等软组织中沉积。长期累积会造成器官钙化，最常见的就是血管钙化。但机体有阻止这种异常沉积的机制，大量研究表明，维生素K 2具有防止钙的这种错误沉积作用。经过羧化的基质γ-羧基谷氨酸蛋白可以阻止钙在血管、软骨等软组织中沉积，并可与血管壁上沉积的钙离子结合，将其移出血管，使动脉钙化得到改善。
因此，本发明优选利用维生素K 2能活化骨钙素，准确抓取错误沉积的钙为核心差异点，以达到靶向阻断和预防心血管钙化的目的。
进一步优选地，所述维生素K 2为MK-7结构，通过有机豆类发酵方法获取，相较于化学合成法，无有机试剂残留，全程绿色，服用更安全；
更进一步优选地，所述MK-7为全反式结构，纯度≥99.5％，反式结构的MK-7生物利用率更高。
所述组成物Ⅲ由提供心血管日常健康保护的活性成分组成，可以包括Ω-3脂肪酸、吡咯喹啉醌(PQQ)、辅酶Q 10(CoQ 10)、表儿茶素、南瓜籽油、磷脂、磷虾油、螺旋藻、槲皮素、蕃茄红素、石榴多酚、白藜芦醇、矢车菊素、大豆异黄酮、大蒜素中的一种或者多种。
辅酶Q 10是一种脂溶性醌，其结构类似于维生素K，因其母核六位上的侧链—聚异戊烯基的聚合度为10而得名，是一种醌环类化合物。有研究表明降胆固醇的他汀类药物，能降低体内辅酶Q 10水平高达40％，让心脏问题变得更加严重。在服用他汀类药物的同时，补充服用辅酶Q 10，可以减少他汀类药物的这种副作用，同时缓解药物引起的肌痛和疲劳，并起到保护肝脏的作用。同时，辅酶Q 10能激活人体细胞和产生能量，具有提高免疫力、增强抗氧化、延缓衰老和增强人体活力等功能。
PQQ是由革兰氏阴性菌产生的，对微生物、动植物具有广泛营养作用，并具备抗 氧化性的营养元素。PQQ对心脏的保护作用与其清除自由基能力有关。PQQ能够清除由缺氧再灌注产生的活性氧，显著降低心脏中乳酸脱氢酶的释放，在黄素还原酶催化作用下，其催化产物还能够降低血红蛋白过氧化状态，消除缺氧再灌注对心肌的损伤。研究显示，使用PQQ保护缺血-再灌注小鼠的心脏，能显著缩小心肌梗死范围，增强左室压力和左室舒张压升降速率，减少心室纤维性颤动，降低心肌组织中丙二醛的水平。PQQ还能抑制过氧化氢诱导的大鼠心肌细胞ROS的产生，以及线粒体膜电位的降低，从而降低氧化应激、抑制线粒体功能的失活，保护大鼠心肌细胞。
为此，本发明针对长期服用他汀类药物体内辅酶Q 10水平降低的特点，优选复配PQQ和CoQ 10，一方面提高体内辅酶Q 10水平，另一方面激活细胞，加强线粒体能量代谢，提高心肌能力，避免药物损伤。同时PQQ和CoQ 10都可以提高机体抗氧化能力，维持清除自由基平衡。
优选地，PQQ可以是吡咯喹啉醌的二钠盐形式，也可以是吡咯喹啉醌的酸形式，纯度≥99％。
优选地，CoQ10的纯度≥98％。
Ω-3是一种长链、多元不饱和脂肪酸，是从植物和海洋生物中发现的。现有研究数据表明Ω-3具有促进心脏健康和预防冠状动脉疾病的功效。其主要通过保护血管内壁细胞、恢复血管弹性、舒张血管、抑制血小板聚集，在降低血脂的同时，还降低血压，抑制血栓的形成，从而有效预防和治疗心脑血管疾病。
此外，Ω-3还能够防止心律失常，起到预防心源性猝死的作用。一项对11000余名冠心病人追踪的临床研究发现：每天服用1～2克的Ω-3不饱和脂肪酸可以显著降低心血管疾病患者的死亡率，尤其是降低心源性猝死的发生率可达45％。
Ω-3脂肪酸主要有三种，包括α-亚麻酸、二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)。EPA可预防中风或心肌梗塞的发生，降低血液胆固醇并预防动脉硬化。DHA具有活化脑细胞的功能，能促进协调神经回路传导作用，维持脑部细胞的正常运作，补充DHA可以改善集中力减低、学习能力障碍、记忆丧失及老年性痴呆等。
同时，Ω-3还有抗击神经系统疾病、预防和抗击癌症、抗炎等作用。因此将Ω-3补充剂作为生活方式干预的一部分用于本发明药物组合物中，可降低人群的死亡率与心源 性猝死风险。
优选地，本发明中，Ω-3脂肪酸中EPA:DHA的比例为(0.1～4)：1；
进一步优选地，Ω-3脂肪酸中EPA的含量≥40％；
更进一步优选地，Ω-3脂肪酸中EPA的含量≥45％。
本发明发现，在本领域中，能全面阻断和预防心血管钙化的活性成分或者膳食补充剂很多，但并不是简单复配就能达到增效目的。为此本发明从钙化的机理及心血管疾病以及他汀类药物代谢特点出发，通过大量试验筛选到上述组分用于复配，一方面可以促进钙的吸收避免血管壁多余钙的积累，另一方面加强已经错误沉积钙的转化，第三方面通过加强线粒体能量代谢，提高心肌能力，增强抵抗，避免机体损伤，进而从宏观上进行提前预防，阻断风险源头和提供预案保护措施。在改善血管钙化的同时，也能预防和消除血管钙化带来的其他风险。
作为本发明的具体实施例之一，所述的一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，含以下质量份的组分：维生素K 2(MK-7)0.01～1份、Ω-3脂肪酸300～3000份、吡咯喹啉醌(PQQ)1～40份、辅酶Q 10(CoQ 10)10～500份、维生素D 3(VD 3)1～60份。
在更优选的实施方案中，所述组合物还包括辅料组分，所述辅料为制备本发明提供的含有维生素K 2(MK-7)改善心血管钙化的药物组合物的必备辅料，包括包衣粉、抗氧化剂、润滑剂、胶囊皮。更优选的是，所述辅料为微晶纤维素、二氧化硅、硬脂酸镁、α-环糊精、甘露糖醇、羧甲基纤维素钠、羟丙基纤维素、甘油、明胶、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、滑石粉、变性淀粉、抗氧化剂、二氧化钛、柠檬黄铝色淀、日落黄铝色淀、胭脂红铝色淀、棕氧化铁、三乙酸甘油酯、聚乙二醇、交联聚维酮、交联羧甲基纤维素钠中的一种或者多种。
所述药物组合物的剂型为片剂、粉剂、硬胶囊、软胶囊、悬浮剂中的一种或者多种。
本发明的第二方面提供了上述含有维生素K 2改善心血管钙化的药物组合物在膳食补充剂、保健品中的应用。
在第三方面，本发明提供了一种软胶囊，所述软胶囊含有上述的含有维生素K 2改善心血管钙化的药物组合物。优选地，所述软胶囊包含以下质量份的组分：维生素K 2 (MK-7)0.01～0.7份、Ω-3脂肪酸500～2500份、吡咯喹啉醌(PQQ)1～30份、辅酶Q 10(CoQ 10)50～500份、维生素D 3(VD 3)1～50份、软胶囊皮50～500份、肠溶包衣粉10～100份、辅料20～200份。
第四方面，本发明提供上述含有维生素K 2(MK-7)改善心血管钙化的药物组合物的制备方法。所述制备方法为：
(1)制粒：在避光条件下，将组成物Ⅱ、组成物Ⅲ中非脂溶性成分与部分辅料混合均匀，采用干法制粒，粒径控制在50～200目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取组成物Ⅲ中脂溶性成分、组成物Ⅰ和辅料中的抗氧化剂，在20～60℃温度下将抗氧化剂和组成物Ⅰ分别溶于组成物Ⅲ中脂溶性成分的油中，得到混合油液，静置4～12h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊
本发明制备方法还包括进一步处理方法，包括但不限定于干燥、洗丸、捡丸、包装等，最终获得成品。
采用本制备方法得到的产品，由于特殊的双重保护方式，避免了光、热、酸等环境的影响以及口腔、胃的首过效应，避免摄入后被过早分解，因此组合物中的MK-7及其他活性成分的活性更稳定持久，生物利用率更高，产品质量更稳定，货架期更长。
本发明第三方面提供上述含有维生素K 2(MK-7)改善心血管钙化的药物组合物在膳食补充剂、保健品中的应用。
以下实施例用于说明本发明，但不用来限制本发明的保护范围。
实施例1
本实施例提供一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.18份、Ω-3脂肪酸1200份、PQQ 10份、辅酶Q 10(CoQ 10)200份、维生素D 3(VD 3)5份、软胶囊皮250份、肠溶包衣粉100份、辅料50份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在100目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.2g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在40℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置12h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
实施例2
本实施例提供一种含有维生素K2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.09份、Ω-3脂肪酸600份、PQQ 10份、辅酶Q 10(CoQ 10)100份、维生素D 3(VD 3)2份、软胶囊皮150份、肠溶包衣粉80份、辅料30份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在120目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.15g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在40℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置12h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
实施例3
本实施例提供一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.12份、Ω-3脂肪酸900份、PQQ 15份、辅酶Q 10(CoQ 10)150份、维生素D 3(VD 3)3份、软胶囊皮180份、肠溶包衣粉70份、辅料40份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在80目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.25g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在50℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置12h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
实施例4
本实施例提供一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.45份、Ω-3脂肪酸1000份、PQQ 12份、辅酶Q 10(CoQ 10)250份、维生素D 3(VD 3)4份、软胶囊皮180份、肠溶包衣粉90份、辅料45份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在100目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.26g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在45℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置8h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
实施例5
本实施例提供一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.65份、Ω-3脂肪酸1300份、PQQ 20份、辅酶Q 10(CoQ 10)200份、维生素D 3(VD 3)5份、软胶囊皮300份、肠溶包衣粉100份、辅料50份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在120目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.3g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在40℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置10h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
实施例6
本实施例提供一种含有维生素K 2(MK-7)改善心血管钙化的药物组合物，按照重量份数计，含有以下重量份的组分：
维生素K 2(MK-7)0.3份、Ω-3脂肪酸1500份、PQQ18份、辅酶Q 10(CoQ 10)180 份、维生素D 3(VD 3)10份、软胶囊皮200份、肠溶包衣粉80份、辅料60份。
其制备方法如下：
(1)制粒：在避光条件下，将MK-7、PQQ与压片辅料等比例混合均匀，采用干法制粒，粒径控制在100目，得到制粒颗粒；
(2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定0.26g重量的裸片；
(3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
(4)囊液:按重量称取Ω-3、CoQ 10、VD 3和抗氧化剂，在40℃温度下将抗氧化剂和CoQ 10、VD 3分别溶于Ω-3油中，得到混合油液，静置11h脱泡得到囊液；
(5)软胶囊皮：软胶囊皮的制备采用本行业通用配方和制备方法制得；
(6)软胶囊：采用特殊设备，将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，通过特殊模具进行压丸，得到内含有片剂的软胶囊。
验证试验
1.组合物中MK-7含量加速稳定性考察
分别取实施例4、实施例5、实施例6制得的软胶囊为实验组，以购得商业化维生素K 2(MK-7)软胶囊(MK-7含量90μg)为对照组，分别装入密封棕色小瓶中。置于40±2℃、75％±5％RH环境的恒温恒湿箱中，做加速实验。在第0、1、2、3、4、5、6、9个月取样，测MK-7的含量。MK-7含量测定采用高效液相色谱法测定。加速稳定性试验结果如下表。
表1 加速稳定性试验
Figure PCTCN2022090653-appb-000001
由表1结果可以看出，实施例4、实施例5、实施例6的组合物中MK-7的含量基本没有变化，维持稳定，但对照组的在加速3个月后就开始衰减。说明本发明的制备方法制备的含有MK-7的药物组合物中，MK-7活性成分能保持较长时间的稳定。按照正常 的加速转化时间计算，常温可以保证至少3年的货架期。
2.药物组合物对大鼠血管钙化的影响
选择SPF级SD雄性大鼠，体态健康，6～8周龄，体重180g-200g。
大鼠按体重随机分为正常对照组(10只)和地塞米松注射组(100只)。地塞米松注射组大鼠肌内注射地塞米松2.5mg/kg，每周3次，正常对照组肌内注射相应容量的生理盐水。连续注射6周后，停止注射。大鼠禁食24h，眼眶静脉取血，分离血清，使用全自动生化分析仪测定大鼠血清碱性磷酸酶(ALP)水平，将地塞米松注射组大鼠的ALP水平与正常对照组大鼠的ALP水平进行比较，评定造模结果。将造模成功的大鼠随机分为5组:模型组、阳性对照组(纯品MK-7100μg/kg)、实验组(实施例4、实施例5、实施例6)。正常对照组和模型组按10mg/kg食用油灌胃，实验组按所设实施例给予对应的MK-7灌胃，阳性对照组每天给予食用油溶解的MK-7(12mg/kg)灌胃，每日1次，连续6周。各组大鼠分笼饲养，自由摄食饮水，室温恒定在(22±2)℃。
观察指标与方法：末次给药后，大鼠禁食24h，眼眶静脉取血，分离血清，采用放射免疫法测定血清OPG、OPN、CaBP、BMP-7水平。
血管钙含量测定:取10mg腹主动脉溶于硝酸消化、烤干，用含有27nmol/L的KCL和27μmol/L的LaCl 3的去离子水复溶，用原子分光光度计在442.7nm处读取吸光度，换算成组织钙含量(μmol/mg.dw)。
统计学方法采用SPSS21.0软件进行统计学分析，计量资料以均数±标准差表示，采用单因素方差分析及Dunnett-t检验进行分析，P＜0.05为差异有统计学意义。
结合图1～图5可以看出药物组合物对大鼠血管钙化的影响。与正常对照组相比，模型组大鼠血清的OPN(血清骨桥蛋白)、OPG(护骨素)、CaBP(钙结合蛋白)及BMP-7(骨形态发生蛋白-7)水平显著降低；与模型组相比，实验组(实施例4)、实验组(实施例5)、实验组(实施例6)大鼠血清的OPN(血清骨桥蛋白)、OPG(护骨素)、CaBP(钙结合蛋白)及BMP-7(骨形态发生蛋白-7)水平显著升高，差异性显著。同时与正常对照组相比，模型组大鼠血管血钙水平显著增加；与模型组相比，实验组(实施例4)、实验组(实施例5)、实验组(实施例6)大鼠血管钙水平显著降低，差异性显著。
而OPN(血清骨桥蛋白)是血管平滑肌由收缩表型向合成表型转化的标志基因， 能抑制培养的血管平滑肌细胞的钙化作用；OPG(骨保护素)可以在血管内皮细胞、平滑肌细胞中表达和释放，通过提高内皮细胞存活来防止炎症细胞因子的血管损害作用，与粥样斑块破裂有关；BMP-7(骨形态蛋白-7)为骨形成蛋白，属于转化生长因子β家族，可以通过抑制血管平滑肌细胞VSMC的增殖，改善血管钙化；钙结合蛋白(CaBP)参与细胞周期调控，细胞增殖分化，血管生成以及细胞外基质重建等多种生命过程，并对心肌细胞具有促进生长和存活作用，可能促进其小肠上段对钙磷的吸收和骨钙的释放、转运能力。
综上，本发明的药物组合物可以通过显著提高OPN(血清骨桥蛋白)、OPG(护骨素)、CaBP(钙结合蛋白)及BMP-7(骨形态发生蛋白-7)水平，来调控抑制血管钙化，进而降低血管钙含量。同时通过实验组与阳性对照组发现，相较于单一化合物，本发明的药物组合物具有复配增效效果。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的方法及技术内容作出些许的更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (12)

  1. 一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述药物组合物由组成物Ⅰ、组成物Ⅱ、组成物Ⅲ构成，其中组成物Ⅰ由具有促进钙吸收的活性功能成分组成，组成物Ⅱ由具有抑制或逆转钙化的活性功能成分组成，组成物Ⅲ由提供心血管健康日常保护的活性功能成分组成；
    所述组成物Ⅰ、组成物Ⅱ、组成物Ⅲ的质量比为(0.1～5)：(0.01～0.5)：(100～500)。
  2. 根据权利要求1所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述组合物Ⅰ由具有促进钙吸收的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，其中主要活性成分为维生素D 3，辅助活性成分为乳糖、维生素A、清蛋白多肽、卵黄蛋白肽、低聚果糖、低聚半乳糖、β-胡萝卜素中的一种或者多种。
  3. 根据权利要求1所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述组合物Ⅱ由具有抑制或者逆转钙化的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，所述主要活性成分为维生素K 2，辅助活性成分为柚皮素、花生四烯酸、雷公藤红素、葛根素、芹菜素、附子多糖中的一种或者多种。
  4. 根据权利要求1所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述组成物Ⅲ由提供心血管日常健康保护的活性成分组成，其中所述活性成分包括主要活性成分和辅助活性成分，主要活性成分为Ω-3脂肪酸、吡咯喹啉醌、辅酶Q 10，辅助活性成分为表儿茶素、南瓜籽油、磷脂、磷虾油、螺旋藻、槲皮素、蕃茄红素、石榴多酚、白藜芦醇、矢车菊素、大豆异黄酮、大蒜素中的一种或者多种。
  5. 根据权利要求1～4中任一项所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述组成物Ⅰ占所述药物组合物总质量的0.1％～1％；所述组成物Ⅱ占所述药物组合物总质量的0.001％～0.1％；所述组成物Ⅲ占所述药物组合物总质量的30％～85％。
  6. 根据权利要求1～4中任一项所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述药物组合物还包括辅料部分，所述辅料为微晶纤维素、二氧化硅、硬脂酸镁、α-环糊精、甘露糖醇、羧甲基纤维素钠、羟丙基纤维素、甘油、明胶、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、滑石粉、变性淀粉、抗氧化剂、二氧化钛、柠檬黄铝色淀、日落黄铝色淀、胭脂红铝色淀、棕氧化铁、三乙酸甘油酯、聚乙二醇、交联聚维酮、交联羧 甲基纤维素钠中的一种或者多种。
  7. 根据权利要求1～4中任一项所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于，所述药物组合物包含以下质量份的主要组分：维生素K 20.01～1份、Ω-3脂肪酸300～3000份、吡咯喹啉醌1～40份、辅酶Q 1010～500份、维生素D 31～60份。
  8. 根据权利要求1～4中任一项所述的一种含有维生素K 2改善心血管钙化的药物组合物，其特征在于：
    所述维生素K 2为具有全反式结构的MK-7形式；
    所述Ω-3脂肪酸中EPA和DHA的比例为(0.1～4)：1。
  9. 根据权利要求1～8中任一项所述的含有维生素K2改善心血管钙化的药物组合物在膳食补充剂、保健品中的应用。
  10. 一种软胶囊，其特征在于所述软胶囊含有根据权利要求1～8中任一项所述的含有维生素K2改善心血管钙化的药物组合物。
  11. 根据权利要求9所述的一种软胶囊，其特征在于，所述软胶囊包含以下质量份的组分：维生素K 20.01～0.7份、Ω-3脂肪酸500～2500份、吡咯喹啉醌1～30份、辅酶Q 1050～500份、维生素D 31～50份、软胶囊皮50～500份、肠溶包衣粉10～100份、辅料20～200份。
  12. 如权利要求10或11所述的软胶囊的制备方法，其特征在于，所述制备方法包括如下步骤：
    (1)制粒：在避光条件下，将根据权利要求1所述的组成物Ⅱ、组成物Ⅲ中非脂溶性成分与部分辅料混合均匀，采用干法制粒，粒径控制在50～200目，得到制粒颗粒；
    (2)压片：将步骤(1)得到的颗粒，使用压片机，制成规定重量的裸片；
    (3)包衣片：将步骤(2)所制的裸片在包衣锅内与肠溶包衣粉混合，按照正常包衣步骤制得包衣片；
    (4)囊液：按重量称取根据权利要求1所述的组成物Ⅲ中的脂溶性成分、根据权利要求1所述的的组成物Ⅰ和根据权利要求6所述的辅料中的抗氧化剂，在20～60℃温度下将抗氧化剂和组成物Ⅰ分别溶于组成物Ⅲ中脂溶性成分的油中，得到混合油液，静置4～12h脱泡得到囊液；
    (5)软胶囊皮：采用本行业通用配方和制备方法制得软胶囊皮；
    (6)软胶囊：将步骤(4)的囊液注入含有步骤(3)的包衣片的两层囊皮之间，压丸，得到内含有片剂的软胶囊。
PCT/CN2022/090653 2022-03-25 2022-04-29 一种含有维生素k 2改善心血管钙化的药物组合物及其制备方法与应用 WO2023178799A1 (zh)

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